The objective of this application is to define the physiological control and the pharmacology of the internal anal sphincter (IAS). Since the IAS plays a key role in continence and defecation, its disorders underlie many clinical disorders, such as fecal incontinence and constipation. Disorders of the IAS may also be involved in a variety of anal diseases, such as hemorrhoids and anal fissures. Disorders of the IAS occur more frequently in the elderly and are of particular importance in this age group. Studies are planned in vivo and in vitro in which activity of the internal anal sphincter will be isolated from those of other muscles, such as the external anal sphincter, by simultaneous electrical and mechanical recordings. The factors which determine the basal tone will be investigated. Specifically, the role of intrinsic myogenic activity, neural and hormonal influences will be evaluated. The chemical transmitters involved in the anorectal reflex (which causes IAS relaxation) and micturition reflex (which causes contraction of the sphincter) will be investigated. These studies will utilize some of the techniques which we have been successfully using in the lower esophageal sphincter. Specifically, the actions and sites of actions of neurotransmitter substances and regulatory peptides will be investigated. Most of these studies will be performed in the opossums, but other animal species will also be used to determine species differences in the control of the sphincter. Some studies are planned in awake animals to understand the normal physiology of the IAS. These studies should provide important information on the physiology and pharmacology of the IAS which may be useful in the understanding of pathophysiology, effects of drugs and treatment of anorectal disorders.